The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

Benner, Chris; Meulen, Talitha van der; Cáceres, Elena; Tigyi, Kristof; Donaldson, Cynthia J.; Huising, Mark O.

doi:10.1186/1471-2164-15-620

Cited by 253 publications

(295 citation statements)

References 74 publications

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“…While ZnT3 mRNA was reported in purified human β cells in one study [38], levels were zero, or at the limit of detection, in samples from several subjects in another [37]. ZnT3 mRNA was similarly barely detected by RNASeq in purified mouse β cells [36], in line with our findings in mouse islets [34]. The role of this particular transporter in controlling β cell Zn 2+ thus remains unclear.…”

Section: Znt Familysupporting

confidence: 82%

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Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

149

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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Section: Znt Familysupporting

confidence: 82%

“…ZnT6 mRNA was detected in the islets of Langerhans [34], its functional heterodimerization with ZnT5 has been described [35], and its presence in purified β cells from both mouse [36] and human [37,38] confirmed by massive parallel sequencing (RNASeq).…”

Section: Znt Familymentioning

confidence: 93%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

149

104

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“…All experiments were performed in human pancreatic islets and the human insulinproducing cell line EndoC-βH1 [24], increasing their translational potential [25][26][27][28]. The data obtained indicate that IFNα is a crucial mediator of excessive inflammation and ER stress in the early steps of type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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“…However, the use of rodent models as a proxy for human disease comes at the risk of identifying signals that protect mouse but not human beta cells against death. For example, systematic comparison of the transcriptomes of purified mouse and human beta cells revealed that human beta cells, in contrast to mouse beta cells, express very few to no receptors for the related cytokines prolactin, GH or ciliary neurotrophic factor [13,14]. This would suggest that potential protective effects of these factors may not translate to human beta cells.…”

Section: Gfpmentioning

confidence: 98%

“…This would suggest that potential protective effects of these factors may not translate to human beta cells. Similarly, mouse beta cells express very high levels of the type 1 IL-1 receptor message and protein (Il1r1/IL1R1) [13], while the expression of IL1R1 in human islets is markedly lower and enriched in non-beta cells [14], which raises the question of whether human beta cells would show an equally robust response to an insult mediated by a cytokine cocktail that included IL-1β. Of course, in most studies on mouse beta cells [4,13] they are isolated from adults whose age is measured in months; a confounder that is difficult to avoid when using mouse beta cells to model diseases of the adult human islet.…”

Section: Gfpmentioning

confidence: 99%

Tuning to the right signal

Huising

2015

Diabetologia

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Pancreatic beta cells are clustered in islets of Langerhans together with alpha cells in an arrangement that facilitates the tight coordination of insulin and glucagon secretion at the source of their release. Other secretory cells, including somatostatin-secreting delta cells and pancreatic polypeptide cells, co-localise with alpha and beta cells in the islet and serve to modulate islet endocrine output. A multitude of non-secretory cell types, including endothelial cells, pericytes, stromal cells, glial cells and macrophages, complete the cellular make up of the islet, which is further enhanced by (para)sympathetic nerve terminals that impinge on the islets via neurotransmitters released in the islet microenvironment. While this islet architecture is relatively simple compared with the vast complexity of the central nervous system, the constellation of cell types united in the islet nevertheless provides a rich substrate for local paracrine and autocrine interactions that affect diverse aspects of islet physiology, ranging from the modulation of hormone secretion to the regulation of islet cell mass via proliferation and death. In this issue of Diabetologia (DOI: 10.1007/s00125-015-3552-5), Yang et al take the notion of rich crosstalk within the islet as their point of departure for a systematic evaluation of the beta cellprotective properties of an extensive panel of over 200 factors, with some surprising and highly interesting results, as discussed in this commentary.

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The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

Cited by 253 publications

References 74 publications

Zinc and diabetes

Zinc and diabetes

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

Tuning to the right signal

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